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O O O OH N O O O jasmine O camphor apple N O chocolate lemon O O O musk HO HO O raspberry peppermint Me vanilla O H H Me O amber O hyacinth eucalyptus NH 2 SH garlic O fish grapefruit O O N marigold fatty H OMe SH H H N O Me O skunk H urine green pepper woody

PEAR O O BANANA O O

THE OLFACTORY SYSTEM AND INSTINCTIVE BEHAVIORS N H S AGGRESSION O O O OH PHEROMONES N MATERNAL BEHAVIOR N O SEXUAL BEHAVIOR N S PREDATOR ODORS FEAR

THE OLFACTORY PATHWAY Olfactory Olfactory Bulb Bulb (OB) Olfactory Epithelium (OE) Olfactory Olfactory cortex Cortex (OC)

THE VOMERONASAL PATHWAY Accessory Olfactory Bulb Vomeronasal Organ (VNO) Medial Amygdala

THE OLFACTORY EPITHELIUM CILIA STRUCTURE mucus cilia supporting cell olfactory sensory B. Menco, 1997 neuron basal stem cell axons to olfactory bulb

THE SEARCH FOR ORs: combinatorial PCR

PCR PRODUCTS PCR PRODUCTS + RESTRICTION ENZYME

TEN OLFACTORY RECEPTORS THE

NOVEL MOTIFS IN OLFACTORY RECEPTORS THE

hypervariable residues

OR GENES: EXPRESSION IN OLFACTORY EPITHELIUM (OE)

OR GENES: A MULTIGENE FAMILY

THE OR GENE FAMILY IN HUMAN AND MOUSE Human Mouse 638 1209 Total OR genes Intact OR genes 363 910 Pseudogenes 275 299 % pseudogenes 43 25

CHROMOSOMAL LOCATIONS OF HUMAN OR GENES

CANDIDATE PHEROMONE RECEPTORS IN THE VOMERONASAL ORGAN V1Rs V2Rs (~120) (~140)

PATTERNS OF OR GENE EXPRESSION IN OLFACTORY EPITHELIUM OR-K20 OR-K21 OR-L45 OR-A16 Zone 4

EXPRESSION ZONES IN THE OLFACTORY EPITHELIUM * * * * * * * * * * * * * * * * * * * * * *

OLFACTORY EPITHELIUM: A MOSAIC OF NEURONS EXPRESSING DIFFERENT ORs

IDENTIFICATION OF ORs FOR SPECIFIC ODORANTS single olfactory sensory neurons odorants calcium imaging single cell RT-PCR cDNAs OR

TEST ODORANTS carboxylic bromocarboxylic dicarboxylic #carbon alcohols Alcohol s Carboxylic Acid s Bromocarboxylic Acid s Dicarboxylic Acid s acids acids acids atoms O O O H O 4 B r C4 OH OH O H OH buta nol * butanedi oic acid * butanoic acid bromobuty ric acid O O O O O 5 C5 OH O H B r OH OH H O pentanedi oic acid * penta nol pentanoic acid bromope ntanoic acid O O O H O 6 C6 Br O H O H OH OH hexanol hexanoic acid bromohexa noic acid hexanedioic a cid O O O O O 7 C7 OH B r O H H O O H OH * hepta nol heptanoic acid bromoheptanoic heptanedi oic acid acid O O O H O 8 Br C8 O H O H O H OH octanol octanoic acid bromooctanoic a cid O octanedioic acid O O O O 9 C9 O H O H Br OH H O O H bromononanoic acid * nona nol nonanoic nonanedioic acid

RESPONSES OF ONE NEURON TO ODORANTS C C C C C C A A A A A A B B B B D D D D 4 5 6 7 8 9 4 5 6 7 8 9 4 5 6 8 6 7 8 9

ODORANTS ARE DETECTED BY COMBINATIONS OF ORS ODORANT RECEPTOR ODORANT

COMBINATORIAL CODING COMBINATORIAL RECEPTOR CODES FOR ODORS ODORANTS RECEPTORS

RECEPTOR CODES AND PERCEPTION ODORANT RECEPTOR

RECEPTOR CODES: THE EFFECT OF CONCENTRATION ODORANT RECEPTOR

ODORANTS PHEROMONES O OH OH OH O O O O OH OH OH rose sweaty aggression subordination ODOR INSTINCTIVE BEHAVIOR

THE OLFACTORY BULB olfactory bulb glomerulus olfactory epithelium To olfactory cortex Mitral cell

AXONS OF NEURONS WITH THE SAME OR CONVERGE IN OLFACTORY BULB

OR-SPECIFIC GLOMERULI IN THE OLFACTORY BULB medial lateral olfactory bulb olfactory bulb M71 A16 M50 0.5 mm

A STEREOTYPED MAP OF OR INPUTS IN THE OLFACTORY BULB

ODOR CODING IN OLFACTORY EPITHELIUM AND BULB O O O H OH OH OH OH OH OE OB ROSE RANCID

THE OLFACTORY CORTEX Anterior Olfactory Piriform Amygdala Entorhinal olfactory tubercle cortex (Amg) cortex nucleus (OT) (PC) (EC) (AON)

HOW ARE OR INPUTS ORGANIZEED IN THE CORTEX?

BARLEY LECTIN: A GENETIC TRANSNEURONAL TRACER Pomp BL PompBL mice olfactory olfactory olfactory epithelium bulb cortex

COEXPRESSION OF BL WITH A SINGLE OR GENE M5iBL mice M50iBL mice gene M5 IRES BL M50 IRES BL (zone 1) (zone 4) M5 IRES BL M50 IRES BL mRNA M5 BL M50 BL protein

BL IN THE OLFACTORY EPITHELIUM AND OLFACTORY BULB olfactory bulb olfactory epithelium olfactory bulb relay neurons M5iBL M50iBL

BL IN OLFACTORY CORTEX PompBL 3.11mm M50iBL-#1 M50iBL-#2 3.15mm 3.15mm 3.15mm

CLUSTERS OF BL+ CORTICAL NEURONS IN M5iBL AND M50iBL MICE anterior piriform cortex PompBL M5iBL M5iBL M50iBL M50iBL M50iBL

CLUSTERS OF BL+ CORTICAL NEURONS IN M5iBL AND M50iBL MICE olfactory tubercle posterior piriform cortex lateral entorhinal cortex M5iBL M5iBL M5iBL M50iBL M50iBL M50iBL

A STEREOTYPED MAP OF OR INPUTS IN OLFACTORY CORTEX

DIVERGENCE AND PARALLEL PROCESSING OF OR INPUTS OE OB OC

BL+ NEURONS IN ANTERIOR PIRIFORM CORTEX PERCENT OF AREA OCCUPIED BY BL+ CLUSTERS M5iBL: 5.7% M50iBL: 4.2% NUMBER OF BL+ NEURONS PompBL: 179,570 ±3935 M50iBL: 4390 ±179 (2.4% of PompBL) M5iBL: 6570 ±217 (3.7% of PompBL)

INPUTS FROM DIFFERENT ORS OVERLAP IN CORTEX OE OB OC

INPUTS FROM DIFFERENT ORS ARE COMBINED IN SINGLE CORTICAL NEURONS OE OB OC

MODEL: CORTICAL NEURONS AS COINCIDENCE DETECTORS OH O O OR1 OR2 OR3 OR4

ACKNOWLEDGMENTS Kerry Ressler Susan Sullivan Hiroaki Matsunami Bettina Malnic Lisa Horowitz Zhihua Zou Jean-Pierre Montmayeur Collaborators: Takaaki Sato Junzo Hirono